The present invention relates generally to synthetic organic chemistry. More particularly, the invention relates to the Claisen rearrangement reaction and to a novel method of performing such reactions in tandem so as to give rise to chiral products. The invention finds utility in the fields of organic synthesis and stereospecific catalysis.
Since its discovery in 1912, the Claisen rearrangement has become one of the most powerful tools for carbon-carbon bond formation in chemical synthesis. See, e.g., Claisen (1912) Chem. Ber. 45:3157; Enders et al. (1996) Tetrahedron: Asymmetry 7:1847; Blechert et al. (1989) Synthesis 71; Kallmerten et al. (1989) Stud. Nat. Prod. Chem. 3:323; Moody et al. (1987) Adv. Heterocycl. Chem. 42:203; and Ziegler et al. (1988) Chem. Rev. 88:1423. The Claisen reaction is a [3,3]-sigmatropic rearrangement, which involves the conversion of an allylic compound, generally an allylic vinyl ether, to an xcex1,xcex2-disubstituted, xcex2,xcex3-unsaturated carbonyl compound. The reaction may be illustrated as follows: 
Allylic aryl ethers also undergo a Claisen rearrangement to give ortho-allylphenols: 
Activation of Claisen reactions has traditionally been accomplished under thermal control, typically at temperatures of 200xc2x0 C. or more. Activation has also been achieved through the incorporation of cationic or anionic charge in the bond reorganization event (see Takai et al. (1981) Tetrahedron Lett. 22:3985; Takai et al. (1984) Bull. Chem. Soc. 57:446; Stevenson et al. (1982) Tetrahedron Lett. 23:3143; and Takai et al. (1984) Tetrahedron 40:4013; Arnold et al. (1949) J. Am. Chem. Soc. 71:1150; Ireland et al. (1973) J. Am. Chem. Soc. 94:5897; Denmark et al. (1982) J. Am. Chem. Soc. 104:4972; Wilson et al. (1984) J. Org. Chem. 49:722; Buchi et al. (1985) J. Org. Chem. 50:4664; and Alker et al. (1 990) J. Chem. Soc. Perkins Trans. 1, 1623). Despite its prolific use in chemical synthesis, very few examples of catalytic Claisen variants have been reported. See Vedejs et al. (1994) J. Am. Chem. Soc. 116:579, pertaining to protic acid (e.g., toluenesulfonic acid) catalysis of a Michael addition reaction, in turn initiating an aza-Claisen rearrangement. See also Saito et al. (1996) Synlett, 720, which describes the use of an aluminum catalyst, aluminum tris(4-bromo-2,6-diphenylphenoxide), in the Claisen rearrangement of allyl vinyl ethers.
In 1978, Bellus and Malherbe reported a ketene-Claisen reaction, in which treatment of an allyl ether with dichloroketene was found to result in the formation of a 1,3-dipolar allyl vinyl ether, which subsequently underwent [3,3]-bond reorganization, as follows: 
(Malherbe et al. (1978) Helv. Chim. Acta 61:3096; Malherbe et al. (1983) J. Org. Chem. 48:860). Subsequently, others have demonstrated utility of tertiary allylic amines in analogous [3,3]-sigmatropic rearrangement reactions. Edstrom et al. (1991) J. Am. Chem. Soc. 113:6690; Kunng et al. (1983) J. Org. Chem. 48:4262; Maruya et al. (1992) J. Chem. Soc., Perkin Trans, 1617; Vedejs et al., supra; Diederich et al. (1995) Angew Chem., Int. Ed. Engl. 34:1026; Deur et al. (1996)J. Org. Chem. 61:2871).
The aforementioned reactions are limited because of the ketene reactant used, as ketenes are highly unstable compounds. Furthermore, prior syntheses are generally not enantioselective; those who have attempted enantioselective Claisen rearrangements have met with substantial difficulties. For example, Corey et al. (1996), J. Am. Chem. Soc. 118:1229, developed an enantioselective Claisen reaction of an allylic ester, but the synthesis required a reaction time of fourteen days. Yamamoto et al. (1995), J. Am. Chem. Soc. 117:1165, also developed an enantioselective Claisen reaction for rearrangement of an allylic vinyl ether, but the synthesis required stoichiometric quantities of an aluminum promoter.
Applicant""s commonly assigned U.S. patent application Ser. No. 09/670,863 for xe2x80x9cLewis Acid-Catalyzed Claisen Rearrangement in the Preparation of Chiral Products,xe2x80x9d filed on even date herewith, now U.S. Pat. No. 6,359,174, addresses the aforementioned need in the art for an improved Claisen reaction that proceeds quickly, can be conducted as a xe2x80x9cone-potxe2x80x9d synthesis, is activated using catalytic quantities of a catalytic composition, and can be used to produce chiral products in enantiomerically pure form. The- present invention provides a similar xe2x80x9cone-potxe2x80x9d synthetic process wherein catalyzed Claisen rearrangement reactions proceed in tandem to produce enantiomerically pure chiral products.
Claisen rearrangements have previously been conducted in tandem with various other reactions. For example, Thyagarajan et al. (1967) Chemistry and Industry, pp. 401-402, report the use of Claisen rearrangements in conjunction with Cope rearrangements. Claisen-cyclization rearrangements are discussed by Kim et al. (1993) Heterocycles 36(3):497-505 and Weiss et al.(1967) Bull. Soc. Chim. Fr. 34:2033-2038. Tandem Claisen-ene rearrangements have been developed by Mikami et al.; see Mikami et al. (1990) J. Am. Chem. Soc. 112:4035-4037, and Mikami et al. (1994) J. Am. Chem. Soc. 116:10948-10954. Mandai et al. (1991) Tet. Lett. 32(28):3399-3400 present a Claisen-aldol rearrangement for use in synthesizing a bicyclo [3.3.0] octane framework.
Successive double Claisen rearrangements (i.e., xe2x80x9ctandemxe2x80x9d C.laisen reactions) have been developed by Hiratani et al. in the synthesis of chelating agents for metal ions. That is, Hiratani et al. (1995), Tet. Lett. 36:5567-5570, and Hiratani et al. (1997), Tet. Lett. 38:8993-8996, describe a tandem Claisen rearrangement in the synthesis of crownophanes (macrocycles containing rigid aromatic moieties linked with flexible oligoethylene glycol moieties) using heat activation, i.e., a reaction temperature of 195xc2x0 C. or 200xc2x0 C. Uzawa et al. (1998) Chem. Lett. 4:307-308 describe a similar reaction wherein a thermally activated, Lewis acid-catalyzed, tandem Claisen reaction is used to prepare phenol-containing macrocyclic compounds. Synthesis of chiral crownophanes using a thermally activated tandem Claisen rearrangement reaction has been described as well; see Tokuhisa et al. (1999) Tet. Lett. 40:8007-8010. These tandem Claisen rearrangement reactions rely on thermal control and, consequently, are not suitable for synthesis of thermally unstable functional groups.
There is accordingly a need in the art for a tandem Claisen rearrangement reaction that proceeds quickly, can be carried out at or near room temperature, can be conducted as a xe2x80x9cone-potxe2x80x9d synthesis, is activated using only catalytic quantities of a catalytic composition, and can be used to produce chiral products in enantiomerically pure form.
It is therefore a primary object of the invention to provide a novel tandem Claisen rearrangement reaction that addresses the above-mentioned need in the art.
It is another object of the invention to provide a method for preparing enantiomerically pure, chiral products via catalyzed Claisen rearrangement reactions that proceed in tandem.
It is still another object of the invention to provide a method for conducting two or more Claisen rearrangement reactions in tandem by reacting an appropriately substituted allylic compound with two or more equivalents of an acid chloride in the presence of a Lewis acid catalyst composition.
It is yet another object of the invention to provide a method for conducting Claisen rearrangement reactions in tandem by reacting an appropriately substituted allylic compound with a first acid chloride in the presence of a Lewis acid catalyst composition, and then reacting the product of the aforementioned reaction with a second acid chloride that may or may not be the same as the first.
It is a further object of the invention to provide such a method wherein the allylic compound is an allylic amine, an allylic ether, or an allylic thioether.
It is still a further object of the invention to provide such a method wherein one of the reactants or the catalyst composition is covalently linked, either directly or indirectly, to the surface of a solid support.
It is an additional object of the invention to provide such a method wherein the position and/or size of substituents on the allylic reactant determines the stereochemistry of the tandem reaction and the reaction product.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one embodiment, then, the invention provides a method for conducting two or more Claisen rearrangement reactions in tandem via Lewis acid catalysis. The method involves reaction of a total of N equivalents of an acid chloride with an allylic reactant (typically an allylic amine, an allylic thioether, or an allylic ether) in the presence of a Lewis acid catalyst composition, wherein N is the number of Claisen rearrangement reactions to proceed in tandem. The Lewis acid catalyst composition is comprised of two catalyst components, a first component composed of a Lewis acid, and a second component composed of a base, either a tertiary amine or a non-nitrogenous base. The allylic reactant is appropriately substituted so as to allow for two or more successive Claisen rearrangement reactions, each successive Claisen rearrangement utilizing the same or different acid chloride. The reaction is conducted under inert, nonaqueous conditions at a temperature typically in the range of approximately xe2x88x92110xc2x0 C. to 200xc2x0 C., and can give rise to a nonracemic, chiral product.
It is to be understood that unless otherwise indicated this invention is not limited to specific reactants, catalyst compositions, or synthetic methods. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
As used in this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, reference to reference to xe2x80x9ca Lewis acidxe2x80x9d includes mixtures of Lewis acids, xe2x80x9ca catalyst compositionxe2x80x9d includes mixtures of catalyst compositions, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
The following definitions pertain to chemical structures, molecular segments and substituents:
As used herein, the phrase xe2x80x9chaving the structurexe2x80x9d is not intended to be limiting and is used in the same way that the term xe2x80x9ccomprisingxe2x80x9d is commonly used. The tern xe2x80x9cindependently selected from the group consisting ofxe2x80x9d is used herein to indicate that the recited elements, e.g., R groups or the like, can be identical or different.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase xe2x80x9coptionally substituted hydrocarbylxe2x80x9d means that a hydrocarbyl moiety may or may not be substituted and that the description includes both unsubstituted hydrocarbyl and hydrocarbyl where there is substitution.
The term xe2x80x9calkylxe2x80x9d as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms. The term xe2x80x9clower alkylxe2x80x9d intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. xe2x80x9cSubstituted alkylxe2x80x9d refers to alkyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing alkylxe2x80x9d and xe2x80x9cheteroalkylxe2x80x9d refer to alkyl in which at least one carbon atom is replaced with a heteroatom.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one double bond, such as ethenyl, n-propenyl, isopropenyl; s-propenyl, 2-propenyl, n-butenyl, isobutenyl, octenyl, decenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 12 carbon atoms. The term xe2x80x9clower alkenylxe2x80x9d intends an alkenyl group of two to six carbon atoms, preferably two to four carbon atoms. xe2x80x9cSubstituted alkenytxe2x80x9d refers to alkenyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing alkenylxe2x80x9d and xe2x80x9cheteroalkenylxe2x80x9d refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one triple bond, such as ethynyl, n-propynyl, n-butynyl, octynyl, decynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 12 carbon atoms. The term xe2x80x9clower alkynylxe2x80x9d intends an alkynyl group of two to six carbon atoms, preferably 2, 3 or 4 carbon atoms. xe2x80x9cSubstituted alkynylxe2x80x9d refers to alkynyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing alkynylxe2x80x9d and xe2x80x9cheteroalkynylxe2x80x9d refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.
The term xe2x80x9calkoxyxe2x80x9d as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an xe2x80x9calkoxyxe2x80x9d group may be represented as xe2x80x94O-alkyl where alkyl is as defined above. A xe2x80x9clower alkoxyxe2x80x9d group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms.
Similarly, the term xe2x80x9calkyl thioxe2x80x9d as used herein intends an alkyl group bound through a single, terminal thioether linkage; that is, an xe2x80x9calkyl thioxe2x80x9d group may be represented as xe2x80x94S-alkyl where alkyl is as defined above. A xe2x80x9clower alkyl thioxe2x80x9d group intends an alkyl thio group containing one to six, more preferably one to four, carbon atoms.
The term xe2x80x9callenylxe2x80x9d is used herein in the conventional sense to refer to a molecular segment having the structure xe2x80x94CHxe2x95x90Cxe2x95x90CH2. An xe2x80x9callenylxe2x80x9d group may be unsubstituted or substituted with one or more non-hydrogen substituents.
The term xe2x80x9carylxe2x80x9d as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. The common linking group may also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine. Preferred aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. In particular embodiments, aryl substituents have 1 to about 200 carbon atoms, typically 1 to about 50 carbon atoms, and preferably 1 to about 20 carbon atoms. xe2x80x9cSubstituted arylxe2x80x9d refers to an aryl moiety substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing arylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d refer to aryl in which at least one carbon atom is replaced with a heteroatom.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group with an aryl substituent, and the term xe2x80x9caralkylenexe2x80x9d refers to an alkylene group with an aryl substituent; the term xe2x80x9calkarylxe2x80x9d refers to an aryl group that has an alkyl substituent, and the term xe2x80x9calkarylenexe2x80x9d refers to an arylene group with an alkyl substituent.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. The terms xe2x80x9chaloalkyl,xe2x80x9d xe2x80x9chaloalkenylxe2x80x9d or xe2x80x9chaloalkynylxe2x80x9d (or xe2x80x9chalogenated alkyl,xe2x80x9d xe2x80x9chalogenated alkenyl,xe2x80x9d xe2x80x9chalogenated aromaticxe2x80x9d or xe2x80x9chalogenated alkynylxe2x80x9d) refers to an alkyl, alkenyl, aromatic or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
The term xe2x80x9cheteroatom-containingxe2x80x9d as in a xe2x80x9cheteroatom-containing hydrocarbyl groupxe2x80x9d refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon. Similarly, the term xe2x80x9cheteroalkylxe2x80x9d refers to an alkyl substituent that is heteroatom-containing, the term xe2x80x9cheterocyclicxe2x80x9d refers to a cyclic substituent that is heteroatom-containing, the term xe2x80x9cheteroarylxe2x80x9d refers to an aryl substituent that is heteroatom-containing, and the like. When the term xe2x80x9cheteroatom-containingxe2x80x9d appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group. That is, the phrase xe2x80x9cheteroatom-containing alkyl, alkenyl and alkynylxe2x80x9d is to be interpreted as xe2x80x9cheteroatom-containing alkyl, heteroatom-containing alkenyl and heteroatom-containing alkynyl.xe2x80x9d
xe2x80x9cHydrocarbylxe2x80x9d refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. The term xe2x80x9clower hydrocarbylxe2x80x9d intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. The term xe2x80x9chydrocarbylenexe2x80x9d intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, or the like. The term xe2x80x9clower hydrocarbylenexe2x80x9d intends a hydrocarbylene group of one to six carbon atoms, preferably one to four carbon atoms. xe2x80x9cSubstituted hydrocarbylxe2x80x9d refers to hydrocarbyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing hydrocarbylxe2x80x9d and xe2x80x9cheterohydrocarbylxe2x80x9d refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly, xe2x80x9csubstituted hydrocarbylenexe2x80x9d refers to hydrocarbylene substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing hydrocarbylenexe2x80x9d and xe2x80x9cheterohydrocarbylenexe2x80x9d refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom.
A xe2x80x9cLewis acidxe2x80x9d refers to any species with a vacant orbital, in contrast to a xe2x80x9cLewis base,xe2x80x9d which refers to a compound with an available pair of electrons, either unshared or in a xcfx80-orbital. Typically, a Lewis acid refers to a compound containing an element that is two electrons short of having a complete valence shell.
By xe2x80x9csubstitutedxe2x80x9d as in xe2x80x9csubstituted hydrocarbyl,xe2x80x9d xe2x80x9csubstituted hydrocarbylene,xe2x80x9d xe2x80x9csubstituted alkyl,xe2x80x9d xe2x80x9csubstituted alkenylxe2x80x9d and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, hydrocarbylene, alkyl, alkenyl or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as hydroxyl, alkoxy, thio, amino, halo, silyl, and the like. When the term xe2x80x9csubstitutedxe2x80x9d appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. That is, the phrase xe2x80x9csubstituted alkyl, alkenyl and alkynylxe2x80x9d is to be interpreted as xe2x80x9csubstituted alkyl, substituted alkenyl and substituted alkynyl.xe2x80x9d Similarly, xe2x80x9coptionally substituted alkyl, alkenyl and alkynylxe2x80x9d is to be interpreted as xe2x80x9coptionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.xe2x80x9d
The term xe2x80x9caminoxe2x80x9d is used herein to refer to the xe2x80x94NH2 group, while xe2x80x9csubstituted aminoxe2x80x9d refers to xe2x80x94NZ1Z2 groups, where each of Z1 and Z2 is independently selected from the group consisting of optionally substituted hydrocarbyl and heteroatom-containing hydrocarbyl, or wherein Z1 and Z2 are linked to form an optionally substituted hydrocarbylene or heteroatom-containing hydrocarbylene bridge.
The term xe2x80x9csulihydrylxe2x80x9d is used herein to refer to the xe2x80x94SH group, while xe2x80x9cthioxe2x80x9d is used herein to refer to the group xe2x80x94SZ1, where Z1 is selected from the group consisting of optionally substituted hydrocarbyl and hetero-containing hydrocarbyl. A compound containing a sulfur atom bound to two Z1 moieties is termed a xe2x80x9cthioether.xe2x80x9d
The term xe2x80x9cchiralxe2x80x9d refers to a structure that does not have an improper rotation axis (Sn), i.e., it belongs to point group Cn or Dn. Such molecules are thus chiral with respect to an axis, plane or center of asymmetry. Preferred xe2x80x9cchiralxe2x80x9d molecules herein are in enantiomerically pure form, such that a particular chiral molecule represents at least about 95 wt. % of the composition in which it is contained, more preferably at least about 99 wt. % of that composition.
The term xe2x80x9cenantioselectivexe2x80x9d refers to a chemical reaction that preferentially results in one enantiomer relative to a second enantiomer, i.e., gives rise to a product in which one enantiomer represents at least about 51 wt. % of the product. Preferably, in the enantioselective reactions herein, the selectively favored enantiomer represents at least about 85 wt. % of the product, optimally at least about 95 wt. % of the product.
As used herein all reference to the elements and groups of the Periodic. Table of the Elements is to the version of the table published by the Handbook of Chemistry and Physics, CRC Press, 1995, which sets forth the new IUPAC system for numbering groups. In the chemical structures herein, the use of bold and dashed lines to denote particular conformation of groups again follows APACE convention. The symbols xe2x80x9cxcex1xe2x80x9d and xe2x80x9cxcex2xe2x80x9d indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn. Thus xe2x80x9cxcex2xe2x80x9d denoted by a broken line, indicates that the group in question is below the general plane of the molecule as drawn, and xe2x80x9cxcex1,xe2x80x9d denoted by a bold line, indicates that the group in question is above the general plane of the molecule as drawn. The bond symbol

refers to a covalent bond that may be either xcex1 or xcex2.
In one embodiment, then, the invention provides a method for conducting a tandem Claisen rearrangement reaction, comprising reacting an allylic reactant with an acid chloride in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component composed of a base, either a tertiary amine or a non-nitrogenous base, wherein the allylic reactant is substituted with at least two functional groups that enable the reactant to undergo at least two successive Claisen rearrangement reactions. The reaction is conducted under inert, nonaqueous conditions at a temperature typically in the range of approximately xe2x88x92110xc2x0 C. to 200xc2x0 C., and can give rise to a nonracemic, chiral product. As will be explained in further detail, the stereochemistry of the reaction product is readily controlled by the stereochemistry of the allylic reactant.
The two-step reaction wherein an allylic reactant is substituted with two functional groups that enable the reactant to undergo two successive Claisen rearrangement reactions proceeds according to schemes 1 and 2. The first of the two Claisen reactions is represented in Scheme 1, while the second is shown in Scheme 2: 
While not wishing to be bound by theory, it is proposed that the allylic reactant (I) and intermediates (III) and (IV) act to convert the acid chlorides (IIa) and (IIb) to ketene intermediates R1xe2x95x90Cxe2x95x90O and R8xe2x95x90Cxe2x95x90O respectively, which then undergo a further Claisen rearrangement reaction with the allylic reactant in Scheme 1 or the allylic intermediates (III) and (IV) in Scheme 2. In compounds (I), (IIa), (IIb), (III), (IV) and (V), the various substituents are as follows:
R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl (e.g., alky1, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.).
Z1 and Z2 are independently N, O or S.
The subscript xe2x80x9cmxe2x80x9d is zero or 1, with the proviso that when Z1 is N, m is 1, and when Z1 is O or S, m is zero. Similarly, n is zero or 1, with the proviso that when Z2 is N, n is 1, and when Z2 is S or O, n is zero.
Q1, Q2, Q3 and Q4 are independently selected from the group consisting of hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), or, when Z1 is N and m is 1, Q1 and Q2 are joined together in a ring structure, generally a five- or six-membered cyclic group such as piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholino, or the like, and similarly, when Z2 is N and n is 1, Q3 and Q4 may be joined together in a ring structure such as a five- or six-membered cyclic group such as piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholino, or the like.
When a reaction involving more than two successive Claisen rearrangements is desired, it will be appreciated that the allylic reactant (I) must then be substituted with at least one additional xe2x88x92ZaQx(Qy)m, group, e.g., one or more of R4, R5, R6 and R7 may be xe2x88x92ZaQx(Qy)m wherein Za is defined as for Z1 and Z2, i.e., Za is N, O or S, and Qx and Qy are defined as for Q1, Q2, Q3 and Q4. It will also be appreciated that such reactions may also include additional disparate acid chloride reactants. Additional allylic functionalities may be present as well.
Preferably, allylic reactant (I) contains at least one allylic amine group, i.e., at least one of Z1 and Z2 is N. Most preferably, allylic reactant (I) is an allylic diamine, i.e., Z1 and Z2 are both N. Examples of preferred allylic reactants include, but are not limited to, the following:
4-[2-(morpholin-4-ylmethyl)prop-2-enyl]morpholine;
4-[(2E)-2-(morpholin-4-ylmethyl)but-2-enyl]morpholine;
4-[(2Z)-2-(morpholin-4-ylethyl)but-2-enyl]morpholine;
4-[(2E)-1-methyl-2-(1-methyl-1-morpholin-4-ylethyl)but-2-enyl]morpholine;
4-[(2E)-1,1,3-trimethyl-2-(1-methyl-1-morpholin4-ylethyl)pent-2-enyl]morpholine;
4-[(2Z)-1,1-dimethyl-2-(morpholin-4-ylphenylmethyl)but-2-enyl]morpholine;
4-[(2E)-2-(chloromorpholin-4-ylmethyl)-1,3-dimethylbut-2-enyl]morpholine;
4-[(2Z)-1-chloro-1,3-dimethyl-2-(morpholin-4-ylphenylmethyl)pent-2-enyl]morpholine;
4-[2-(piperidylmethyl)prop-2-enyl]morpholine;
4-[(2Z)-2-(piperidylmethyl)but-2-enyl]morpholine;
4-[(2Z)-1-methyl-2-(piperidylmethyl)but-2-enyl]morpholine;
4-[(2E)-1,1-dimethyl-2-(piperidylethyl)but-2-enyl]morpholine;
4-[(2Z)-1,1,3-trimethyl-2-(1-methyl-1-piperidylethyl)pent-2-enyl]morpholine;
4-[(2Z)-1,1-dimethyl-2-(phenylpiperidylmethyl)but-2-enyl]morpholine;
4-[(2E)-2-(chloropiperidylmethyl)-1,3-dimethylbut-2-enyl]morpholine;
4-[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpiperidylmethyl)pent-2-enyl]morholine;
4-[2-(piperazinylmethyl)prop-2-enyl]morpholine;
4-[(2Z)-2-(piperazinylmethyl)but-2-enyl]morpholine;
4-[(2Z)-1-methyl-2-(piperazinylmethyl)but-2-enyl]morpholine;
4-[(2E)-1,1-dimethyl-2-(piperazinylethyl)but-2-enyl]morpholine;
4-[(2Z)-1,1,3-trimethyl-2-(1-methyl-1-piperazinylethyl)pent-2-enyl]morpholine;
4-[(2Z)-1,1-dimethyl-2-(phenylpiperazinylmethyl)but-2-enyl]morpholine;
4-[(2E)-2-(chloropiperazinylmethyl)-1,3-dimethylbut-2-enyl]morpholine;
4-[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpiperazinylmethyl)pent-2-enyl]morpholine;
4-[2-(pyrroidinylmethyl)prop-2-enyl]morpholine;
4-[(2Z)-2-(pyrrolidinylmethyl)but-2-enyl]morpholine;
4-[(2Z)-1-methy-2-(pyrrolidinylmethyl)but-2-enyl]morpholine;
4-[(2E)-1,1-dimethyl-2-(pyrrolidinylethyl)but-2-enyl]morpholine;
4-[(2Z)-1,1,3-trimethyl-2-(1-methyl-1-pyrrolidinylethyl)pent-2-enyl]morpholine;
4-[(2Z)-1,1-dimethyl-2-(phenylpyrrolidinylmethyl)but-2-enyl]morpholine;
4-[(2E)-2-(chloropyrrolidinylmethyl)-1,3-dimethylbut-2-enyl]morpholine;
4-[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpyrrolidinylmethyl)pent-2-enyl]morpholine;
4-[2-(imidazolidinylmethyl)prop-2-enyl]morpholine;
4-[(2E)-2-(imidazolidinylmethyl)but-2-enyl]morpholine;
4-[(2Z)-2-(imidazolidinylmethyl)-1-methylbut-2-enyl]morpholine;
4-[(2E)-2-(imidazolidinylethyl)-1,1-dimethylbut-2-enyl]morpholine;
4-[(2E)-2-(1-imidazolidinyl-isopropyl )-1,1,3-trimethylpent-2-enyl]morpholine;
4-[(2Z)-2-(imidazolidinyiphenylmethyl)-1,1,1-dimethylbut-2-enyl]morpholine;
4-[(2Z)-1-chloro-2-(imidazolidinylphenylmethyl) -1,3-dimethylpent-2-enyl]morpholine;
4-(2-azidomethyl-allyl)-morpholine;
4-(2-azidomethyl-but-2-enyl)-morpholine;
4-(3-azidomethyl-pent-3-enyl)-morpholine;
4-(2-azidomethyl-1,1-dimethyl-but-2-enyl)-morpholine;
4-(2-azidomethyl-1,1,3-trimethyl-pent-2-enyl)-morpholine;
4-[2-(azido-phenyl-methyl)-1,1-dimethyl-but-2-enyl]-morpholine;
4-[2-(azido-chloro-methyl)-1,3-dimethyl-but-2-enyl]-morpholine;
4-[2-(azido-phenyl-methyl)-1-chloro-1,3-dimethyl-pent-2-enyl]-morpholine;
[2-(piperidylmethyl)prop-2-enyl]piperidine;
[(2E)-2-(piperidylmethyl)but-2-enyl]piperidine;
[(2Z)-2-(piperidylethyl)but-2-enyl]piperidine;
[(2E)-1-methyl-2-(1-methyl-1-piperidylethyl)but-2-enyl]piperidine;
[(2E)-1,1,3-trimethyl-2-(1-methyl-1-piperidylethyl)pent-2-enyl]piperidine;
[(2Z)-1,3I -dimethyl-2-(phenylpiperidylmethyl)but-2-enyl]piperidine;
[(2E)-2-(chloropiperidylmethyl)-1,3-dimethylbut-2-enyl]piperidine;
[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpiperidylmethyl)pent-2-enyl]piperidine;
[2-(piperidylmethyl)prop-2-enyl]piperazine;
[(2E)-2-(piperidylmethyl)but-2-enyl]piperazine;
[(2Z)-2-(piperidylethyl)but-2-enyl]piperazine;
[(2E)-1-methyl-2-(1-methyl-1-piperidylethyl)but-2-enyl]piperazine;
[(2E)-1,1,3-trimethyl-2-(1-methyl-1-piperidylethyl)pent-2-enyl]piperazine;
[(2Z)-2-(1-methyl-1-piperidylethyl)-1-phenylbut-2-enyl]piperazine;
[(2E)-1-chloro-3-methyl-2-(piperidylethyl)but-2-enyl]piperazine;
[(2Z)-2-(1-chloro-1-piperidylethyl)-3-methyl-1-phenylpent-2-enyl]piperazine;
[2-(pyrrolidinylmethyl)prop-2-enyl]piperidine;
[(2E)-2-(pyrrolidinylmethyl)but-2-enyl]piperidine;
[(2Z)-1-methyl-2-(pyrrolidinylmethyl)but-2-enyl]piperidine;
[(2E)-1,1-dimethyl-2-(pyrrolidinylethyl)but-2-enyl]piperidine;
[(2E)-1,1,3-trimethyl-2-(1-methyl-1-pyrrolidinylethyl)pent-2-enyl]piperidine;
[(2Z)-1,1-dimethyl-2-(phenylpyrrolidinylmethyl)but-2-enyl]piperidine;
[(2E)-2-(chloropyrrolidinylmethyl)-1,3-dimethylbut-2-enyl]piperidine;
[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpyrrolidinylmethyl)pent-2-enyl]piperidine;
[2-(piperidylmethyl)prop-2-enyl]imidazolidine;
[(2E)-2-(piperidylmethyl)but-2-enyl]imidazolidine;
[(2Z)-2-(piperidylethyl)but-2-enyl]imidazolidine;
[(2E)-1-methyl-2-(1-methyl-1-piperidyletmyl)but-2-enyl]imidazolidine;
[(2E)-1,1,3-trimethyl-2-(1-methyl-1-piperidylethyl)pent-2-enyl] imidazolidine;
[(2Z)-2-(1-methyl-1-piperidylethyl)-1-phenylbut-2-enyl]imidazolidine;
[(2E)-1-chloro-3-methyl-2-piperidylethyl)but-2-enyl]imidazolidine;
[(2Z)-2-(1-chloro-1-piperidylethyl)-3-methyl-1-phenylpent-2-enyl]imidazolidine;
1-(2-azidomethyl-allyl)-piperidine;
1-(2-azidomethyl-but-2-enyl)-piperidine;
1-(3-azidomethyl-pent-3-enyl)-piperidine;
1-(2-azidomethyl-1,1-dimethyl-but-2-enyl)-piperidine;
1-(2-azidomethyl-1,1,3-trimethyl-bent-2-enyl)-piperidine;
1-[2-(azido-phenyl-methyl)-1-dimethyl-but-2-enyl]-piperidine;
1-[2-(azido-chloro-methyl)-1,3-dimethyl-but-2-enyl]-piperidine;
1-[2-(azido-phenyl-methyl)-1-chloro-1,3-dimethyl-pent-2-enyl]-piperidine;
[2-(piperazinylmethyl)prop-2-enyl]piperazine;
[(2E)-2-(piperazinylmethyl)but-2-enyl]piperazine;
[(2Z)-2-(piperazinylethyl)but-2-enyl]piperazine;
[(2E)-1-methyl-2-(1-methyl-1-piperazinylethyl)but-2-enyl]piperazine;
[(2E)-1,1,3-trimethyl-2-(1-methyl-1-piperazinylethyl)pent-2-enyl]piperazine;
[(2Z)-1,1-dimethyl-2-(phenylpiperazinylmethyl)but-2-enyl]piperazine;
[(2E)-2-(chloropiperazinylmethyl)-1,3-dimethylbut-2-enyl]piperazine;
[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpiperazinylmethyl)pent-2-enyl]piperazine;
[2-pyrrolidinylmethyl)prop-2-enyl]piperazine;
[(2Z)-2-(pyrrolidinylmethyl)but-2-enyl]piperazine;
[(2Z)-1-methyl-2-(pyrrolidinylmethyl)but-2-enyl]piperazine;
[(2E)-1,1-dimethyl-2-(pyrrolidinylethyl)but-2-enyl]piperazine;
[(2Z)-1,1,3-trimethyl-2-(1-methyl-1-pyrrolidinylethyl)pent-2-enyl]piperazine;
[(2Z)-1,1-dimethyl-2-(phenylpyrrolidinylmethyl)but-2-enyl]piperazine;
[(2E)-2-(chloropyrrolidinylmethyl)-1,3-dimethylbut-2-enyl]piperazine;
[(2Z)-1-choro-1,3-dimethyl-2-(phenylpyrrolidinylmethyl)pent-2-enyl]piperazine;
[2-(imidazolidinylmethyl)prop-2-enyl]piperazine;
[(2E)-2-(imidazolidinylmethyl)but-2-enyl]piperazine;
[(2Z)-2-(imidazolidinylmethyl)-1-methylbut-2-enyl]piperazine;
[(2E)-2-(imidazolidinylethyl)-1,1-dimethylbut-2-enyl]piperazine;
[(2E)-2-(1-imidazolidinyl-isopropyl)-1,1,3-trimethylpent-2-enyl]piperazine;
[(2Z)-2-(imidazolidinylphenylmethyl)-1,1-dimethylbut-2-enyl]piperazine;
[(2E)-2-(chloroimidazolidinylmethyl)-1,3-dimethylbut-2-enyl]piperazine;
[(2Z)-1-chloro-2-(imidazolidinylphenylmethyl)-1,3-dimethylpent-2-enyl]piperazine;
1-(2-azidomethyl-allyl)-piperazine;
1-(2-azidomethyl-but-2-enyl)-piperazine;
1-(3-azidomethyl-pent-3-enyl)-piperazine;
1-(2-azidomethyl-1,1-dimethyl-but-2-enyl)-piperazine;
1-(2-azidomethyl-1,1,3-trimethyl-pent-2-enyl)-piperazine;
1-[2-(azido-phenyl-methyl)-1,1-dimethyl-but-2-enyl]-piperazine;
1-[2-(azido-chloro-methyl)-1,3-dimethyl-but-2-enyl]-piperazine;
1-[2-(azido-phenyl-methyl)-1-chloro-1,3-dimethyl-pent-2-enyl]-piperazine;
[2-(pyrrolidinylmethyl)prop-2-enyl]pyrrolidine;
[(2E)-2-(pyrrolidinylmethyl)but-2-enyl]pyrrolidine;
[(2Z)-2-(pyrrolidinylethyl)but-2-enyl]pyrrolidine;
[(2E)-1-methyl-2-(1-methyl-1-pyrrolidinylethyl)but-2-enyl]pyrrolidine;
[(2E)-1,1,3-trimethyl-2-(1-methyl-1-pyrrolidinylethyl)pent-2-enyl]pyrrolidine;
[(2Z)-1,1-dimethyl-2-(phenylpyrrolidinylmethyl)but-2-enyl]pyrrolidine;
[(2E)-2-(chloropyrrolidinylmethyl)-1,3-dimethylbut-2-enyl]pyrrolidine;
[(2Z)-1-chloro-1,3-dimethyl-2-(phenylpyrrolidinylmethyl)pent-2-enyl]pyrrolidine;
[2-(pyrrolidinylmethyl)prop-2-enyl]imidazolidine;
[(2E)-2-pyrrolidinylmethyl)but-2-enyl]imidazolidine;
[(2Z)-2-(pyrrolidinylethyl)but-2-enyl]imidazolidine;
[(2E)-1-methyl-2-(1-methyl-1-pyrrolidinylethyl)but-2-enyl]imidazolidine;
[(2E)-1,3-trimethyl-2-(1-methyl-1-pyrrolidinylethyl)pent-2-enyl]imidazolidine;
[(2Z)-2-(1-methyl-1-pyrrolidinylethyl)-1-phenylbut-2-enyl]imidazolidine;
[(2E)-1-chloro-3-methyl-2-(pyrrolidinylethyl)but-2-enyl]imidazolidine;
[(2Z)-2-(1-chloro-1-pyrrolidinylethyl)-3-methyl-1-phenylpent-2-enyl]imidazolidine;
1-(2-azidomethyl-allyl)-pyrrolidine;
1-(2-azidomethyl-but-2-enyl)-pyrrolidine;
1-(3-azidomethyl-pent-3-enyl)-pyrrolidine;
1-(2-azidomethyl-1,1-dimethyl-but-2-enyl)-pyrrolidine;
1-(2-azidomethyl-1,1,3-trimethyl-pent-2-enyl)-pyrrolidine;
1-[2-(azido-phenyl-methyl)-1,1-dimethyl-but-2-enyl]-pyrrolidine;
1-[2-(azido-chloro-methyl)-1,3-dimethyl-but-2-enyl]-pyrrolidine;
1-[2-(azido-phenyl-methyl)-1-chloro-1,3-dimethyl-pent-2-enyl]-pyrrolidine;
[2-(imidazolidinylmethyl)prop-2-enyl]imidazolidine;
[(2E)-2-(imidazolidinylmethyl)but-2-enyl]imidazolidine;
[(2Z)-2-(imidazolidinylethyl)but-2-enyl]imidazolidine;
[(2E)-2-(1-imidazolidinyl-isopropyl)-1-methylbut-2-enyl]imidazolidine;
[(2E)-2-(1-imidazolidinyl-isopropyl)-1,1,3-trimethylpent-2-enyl]imidazolidine;
[(2Z)-2-(imidazolidinylphenylmethyl)-1,1-dimethylbut-2-enyl]imidazolidine;
[(2E)-2-(chloroimidazolidinylmethyl)-1,3-dimethylbut-2-enyl]imidazolidine;
[(2Z)-1-chloro-2-(imidazolidinylphenylmethyl)-1,3-dimethylpent-2-enyl]imidazolidine;
2-(2-azidomethyl-allyl)-imidazolidine;
2-(2-azidomethyl-but-2-enyl)-imidazolidine;
2-(3-azidomethyl-pent-3-enyl)-imidazolidine;
2-(2-azidomethyl-1,1-dimethyl-but-2-enyl)-imidazolidine;
2-(2-azidomethyl-1,1,3-trimethyl-pent-2-enyl)-imidazolidine;
2-[2-(azido-phenyl-methyl)-1,1-dimethyl-but-2-enyl]-imidazolidine;
2-[2-(azido-chloro-methyl)-1,3-dimethyl-but-2-enyl]-imidazolidine;
2-[2-(azido-phenyl-methyl)-1-chloro-1,3-dimethyl-pent-2-enyl]-imidazolidine;
3-azido-2-azidomethyl-propene;
1-azido-2-azidomethyl-but-2-ene;
5-azido-3-azidomethyl-pent-2-ene;
4-azido-3-azidomethyl-4-methyl-pent-2-ene;
2-azido-3-azidomethyl-2,4-dimethyl-hex-3-ene;
(1,3-diazido-2-tert-butyl-allyl)-benzene;
4-azido-3-(azido-chloro-methyl)-2-methyl-pent-2-ene; and
[1-azido-2-(1-azido-1-chloro-ethyl)-3-methyl-pent-2-enyl]-benzene.
The acid chlorides (IIa) and (IIb) may be any acid chlorides that are suitable for undergoing the rearrangement reaction with the allylic reactant (I) as illustrated in Scheme 1. Acid chlorides (IIa) and (IIb) may be the same or different, i.e., R1 and R8 may be the same or different. R1 and R8, as noted earlier herein, are hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), or substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), and is preferably hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl. Most preferably, R1 and R8 are alkyl (with lower alkyl substituents such as methyl being optimal), benzyloxy or thiophenyl.
Examples of suitable acid chlorides thus include, but are not limited to, propanoyl chloride, 2-methylpropanoyl chloride, 2-ethylpropanoyl chloride, 2-cyclohexylpropanoyl chloride, 2-phenylpropanoyl chloride, butanoyl chloride, 2-methylbutanoyl chloride, 2-ethylbutanoyl chloride, 2-cyclohexylbutanoyl chloride, 2-phenylbutanoyl chloride, 3-methylbutanoyl chloride, 3-ethylbutanoyl chloride, 3-cyclohexylbutanoyl chloride, 3-phenylbutanoyl chloride, 2-(phenylmethoxy)acetyl chloride, 2-(p-methylphenylmethoxy)-acetylchloride, 2-(p-ethylphenylmethoxy)acetylchloride, 2-(p-nitrophenylmethoxy)acetyl-chloride, 2-(o-methylphenylmethoxy)acetylchloride, 2-(o-ethylphenylmethoxy)acetylchloride, 2-(o-nitrophenylmethoxy)acetylchloride, 2-phenylthioacetyl chloride, 2-(o-ethylphenyl)thioacetyl chloride, 2-(m-methylphenylmethoxy)acetylchloride, 2-(o-ethylphenylmethoxy)acetylchloride, 2-(m-nitrophenylmethoxy)acetylchloride, 2-phenylthioacetyl chloride, 2-(p-ethylphenyl)thioacetyl chloride, 2-(-pethylphenyl)thioacetyl chloride, 2-(nitrophenyl)thioacetyl chloride, 2-(o-methylphenyl)thioacetyl chloride, 2-(o-ethylphenyl)thioacetyl chloride, 2-(o-nitrophenyl)thioacetyl chloride, 2-(m-methylphenyl)thioacetyl chloride, 2-(m-ethylphenyl)thioacetyl chloride, 2-(m-nitrophenyl)thioacetyl chloride, and the like.
The catalyst composition comprises two catalyst components, a first component composed of a Lewis acid, and a second component composed of a base, either a tertiary amine or a non-nitrogenous base. Suitable Lewis acids generally have the structural formula (VII)
M(X)a(Y)bxe2x80x83xe2x80x83(VII)
wherein M is a metal, X is halide or halide-containing (e.g., SbF6xe2x88x92, BF4xe2x88x92), or is lower alkoxy, fluorinated lower alkoxy (e.g., OCF3, OCF2CF3, OCH2CF3), sulfate, acetate, trifluoroacetate, or triflate (i.e., trifluoromethylsulfonate, or xe2x80x94OSO2CF3), Y is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, or an oxygen-containing or nitrogen-containing organic ligand, a is an integer of 1 or more, and the sum of a and b is in the range of 2 to nmax, where nmax is the number of atoms that can bind to M through single covalent or coordination bonds. However, if Y is a bidentate (or multidentate) ligand, obviously it will be the sum of a and 2b (or xb, where x is the number of covalent or coordination bonds linking Y to M) that is in the range of 2 to nmax. For example, for titanium (M) having two chloro (X) substituents, a single bidentate ligand Y or two monodentate ligands Y may be present, insofar as nmax for titanium is 4, and a, by virtue of the two chloro substituents, is 2. Thus, in the foregoing example, for a monodentate ligand Y, b will be (2 to nmax)xe2x80x94a, i.e., zero to 2, while for a bidentate ligand Y, b will be xc2xd ((2 to nmax)xe2x80x94a, i.e., zero or 1.
The metal M may be any metal in the Periodic Table of the Elements. Preferably, the metal is selected from the group consisting of Groups 2 through 13 of the Periodic Table of the Elements and the lanthanides. More preferred metals are Ti, Mg, Al, Sc, Y, Ni, Cu, Zn and Yb, and most preferred metals are Ti, Mg and Al.
Preferred X moieties are halide and triflate. Thus, X may be chloro, bromo, fluoro or iodo, but is typically chloro or bromo, and most preferably is chloro. Y may be, for example, alkyl, particularly lower alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, etc.), aryl (e.g., phenyl, benzyl), aryloxy (e.g., benzyloxy), or the like, or may be a nitrogen-containing or oxygen-containing organic ligand. One example of a suitable oxygen-containing organic ligand is tetrakis-3,5-bis(trifluoromethyl)-phenylborate, commonly referred to as xe2x80x9cBARF.xe2x80x9d Exemplary nitrogen-containing ligands are unsaturated nitrogen-containing ligands such as (VIIIa) and (VIIIb) 
wherein L is a hydrocarbylene, substituled hydrocarbylene, heteroatom-containing hydrocarbylene, substituted heteroatom-containing hydrocarbylene or heteroatom linkage, R9, R10, R11 and R12 are as defined for R1 through R6, and wherein R9 and R10 and/or R11 and R12 may be linked to form a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene bridge. Preferred subsets of such ligands have the structure (IXa) and (IXb) 
wherein R13 is as defined for R9, R10 and R12, and z is an integer in the range of zero to 5 inclusive. Such ligands include, for example, those having the structural formula (X), wherein R14, R15, R16 and R17 are defined as for R13, with one specific such ligand, 4-[2-(3,4-dichlorophenyl)(1,3-oxazolin-4-yl)]-1-methoxybenzene, shown in structural formula (XI) 
in which case a corresponding titanium catalyst component might have the structural formula (XII) 
The second component of the catalyst composition is a base, either a tertiary amine or a non-nitrogenous base. Tertiary amines will have the structure NR18R19R20 wherein R18, R19 and R20 are independently hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl, or wherein two of R18, R19 and R20 are linked to form a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene or substituted heteroatom-containing hydrocarbylene bridge. Preferred R18, R19 and R20 substituents are alkyl, e.g., lower alkyl. Other useful tertiary amines are nitrogen-containing heterocycles in which at least one nitrogen heteroatom is in the form xe2x80x94Nxe2x95x90, as in, for example, pyridine. Examples of tertiary amines suitable as the second catalyst component thus include, but are not limited to, trimethylamine, triethylamine, methyldiethylamine, ethyldimethylamine, methyldiisopropylamine, dimethylisopropylamine, ethyldiisopropylamine, diethylisopropylamine, N-methylpyrrolidine, N-vinylpyrrolidine, N-methylpyridazine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 2,6-di-t-butyl-4-methylpyridine, N-methylimidazole, etc.
Non-nitrogenous bases that may serve as the second component of the catalyst composition include, without limitation, inorganic hydroxides, inorganic oxides, and metal carbonates. Inorganic hydroxides include, for example, ammonium hydroxide, alkali metal hydroxide and alkaline earth metal hydroxides, such as sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and the like. Inorganic oxides include, for example, magnesium oxide, calcium oxide, and the like. Metal carbonates include sodium carbonate and potassium carbonate. Preferred non-nitrogenous bases are metal hydroxides such as sodium and potassium hydroxide and metal carbonates such as sodium and potassium carbonate.
Procedurally, the reaction is carried out as follows when a single acid chloride is used. The Lewis acid component (VII) of the catalyst composition is combined with the allylic reactant (I) in a suitable solvent, e.g., an aliphatic hydrocarbon, an aromatic hydrocarbon, a halohydrocarbon, an ether, a cyclic ether, or the like. Suitable hydrocarbon solvents include isobutane, butane, pentane, hexane, octane, cyclohexane, methylcyclohexane, benzene, toluene, and the like. Preferred solvents are polar organic solvents, including halohydrocarbons, ethers, and the like, and particularly preferred solvents include such methylene chloride, tetrahydrofuran, diethylether, dimethylether, diisopropylether, dimethoxymethane, dioxane, acetone, methyl ethyl ketone, isobutyl methyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile and chloroform. Methylene chloride is most preferred. Solvents may be used alone or in combination.
The tertiary amine or non-nitrogenous base component of the catalyst composition is then added to the reaction mixture, followed by addition of approximately N equivalents of the acid chloride (IIa) wherein N is the number of successive Claisen rearrangement reactions that are desired (note that N is also the number of functional groups on the allylic reactant that enable the reactant to undergo Claisen rearrangement). Preferably, although not necessarily, N is 2. The reaction is continued until the acid chloride is consumed. Consumption of the acid chloride may be determined using, for example, thin layer chromatography. Generally, the reaction is complete within about 2 to 48 hours, typically within about 2 to 6 hours. After completion, the product is recovered using any suitable means known to those skilled in the art. The recovery process can include separation of by-products, if any, and evaporation of the solvent. The product may be recovered, for example, by extraction, recrystallization, filtration, or other purification processes known in the art.
When two or more different acid chlorides are used, the reaction is carried out by combining the Lewis acid component (VII) with the allylic reactant in a suitable solvent as described above, followed by addition of the tertiary amine or non-nitrogenous base component of the catalyst composition and one equivalent of a first acid chloride, i.e., an acid chloride having the structure (IIa). This results in a single Claisen rearrangement reaction and intermediates (III) and (IV). Then, a second acid chloride is added, i.e., an acid chloride having the structure (IIb). A second rearrangement reaction results in products (V) and (VI). Additional acid chlorides may be added when the allylic reactant (I) is substituted with additional xe2x80x94ZaQx(Qy)m groups, resulting in additional Claisen rearrangement reactions. Alternatively, the allylic reactant (I) may be combined with two or more acid chlorides simultaneously.
The catalytic reaction is preferably although not necessarily homogeneous, and may be carried out in batch, semi-continuously or continuously, under inert, nonaqueous conditions (e.g., under an atmosphere of dry nitrogen and in an organic, completely nonaqueous solvent), at autogenous pressure or higher, depending, for example, on the nature of the catalyst composition and reactants used. The reaction temperature will generally be in the range of about xe2x88x92100xc2x0 C. to 200xc2x0 C., preferably in the range of about xe2x88x9278xc2x0 C. to 100xc2x0 C., most preferably in the range of about 0xc2x0 C. to 50xc2x0 C.; the reaction may be conveniently carried out at room temperature. The amount of total catalyst compositionxe2x80x94i.e., the total of the Lewis acid component and the tertiary amine or non-nitrogenous base componentxe2x80x94is generally in the range of 5 mole % to 300 mole % relative to the allylic reactant (I), the molar ratio of the Lewis acid component to the base component in the catalyst composition is generally in the range of about 1:2 to 2:1, preferably in the range of about 1.25:1 to 1:1.25, and the molar ratio of the reactants, i.e., the molar ratio of the allylic reactant (I) to the acid chloride (II), is typically in the range of about 1:10 to 10:1, preferably in the range of about 1:2 to 2:1, and most preferably is about 1:1.
The novel Claisen rearrangement reaction can also be carried out on a solid support, using solid phase synthesis techniques. Solid-phase synthesis enables use of the reaction in combinatorial chemistry processes, wherein an array or xe2x80x9cmatrixxe2x80x9d of reactions are conducted in parallel on a single substrate. In this embodiment, the allylic reactant (I), the acid chloride (II), or the catalyst is bound either directly or indirectly to the surface of a solid substrate, if indirectly, through a cleavable or noncleavable linker. For example, the allylic reactant (I) can be linked to the surface of a substrate through R6, Q1, Q2, or the like, and the acid chloride (II) can be linked to the surface of a substrate through the methylene group linking R1 to the carbonyl moiety. Any solid support may be used. Typical substrates are those conventionally used in solid phase chemistry and which allow for chemical synthesis thereon. The only limitation upon the materials useful for constructing substrates is that they must be compatible with the reaction conditions to which they are exposed. Suitable substrates useful in practicing the methods of the invention include, but are not limited to, organic and inorganic polymers (e.g., polyethylene, polypropylene, polystyrene, polytetrafluoroethylene), metal oxides (e.g., silica, alumina), mixed metal oxides, metal halides (e.g., magnesium chloride), minerals, quartz, zeolites, and the like. Other substrate materials will be apparent to those of skill in the art.
The present invention thus represents an important contribution to the field of synthetic organic chemistry by providing an entirely new method for conducting Claisen rearrangement reactions using Lewis acid catalysis and at least one acid chloride as a reactant. The present process is useful in conjunction with an enormous variety of reactants and Lewis acid catalyst compositions, and, importantly, can be carried out at room temperature using a xe2x80x9cone-potxe2x80x9d synthesis to prepare chiral compounds in enantiomerically pure form having a specific and predetermined stereochemistry. That is, such reaction products are xe2x80x9cchiralxe2x80x9d compounds. The stereochemistry of the product, i.e., the positioning of R2, R3, R4,R5, R6 and R7 in the reaction products (V) and (VI) 
is determined by the positioning or size of those substituents in the allylic reactant. That is, in allylic reactants having the structure (I) 
either (a) R2 is cis to the carbon atom bound to C(R4R5) and trans to the carbon atom bound to C(R6R7), and R3 is trans to the carbon atom bound to C(R4R5) and cis to the carbon atom bound to C(R6R7), or (b) the converse is true, i.e., R2 is trans and R3 is cis to the carbon atom bound to C(R4R5)and so forth. The former compounds have the structure (Ia) 
and the latter group of compounds have the structure (Ib) 
Assuming that R2 is a sterically bulkier substituent than R3, reaction of compound (Ia) with the acid chloride (IIa) 
will give rise to the intermediates (IIa) and (IVa) 
while reaction of compound (Ib) with the acid chloride (IIa) gives rise to the intermediates (IIIb) and (IVb) 
Thus, a bulky R2 substituent in a cis configuration would result in an anti configuration in relation to the R1 substituent in the product, while a trans R2 substituent would result in a syn configuration. Due to steric interactions, the syn configuration is selectively preferred and intermediates (IIb) and (IVb) will be the predominant intermediate species, i.e., a syn configuration of the sterically bulkier substituent of R2 and R3, and the substituent R1 will be favored. Selectivity between the (IIIb) and (1Vb) intermediates may be achieved by utilizing different Z1Q1(Q2)mand Z2Q3(Q4)n moieties. For example, should intermediate (IIIb) be preferred, Z1 could be N and Z2 could be S. The thioether moiety will be less reactive and Claisen rearrangement on the Z1 side of the allylic reactant will be favored. The subsequent Claisen rearrangement on the Z2 side of the allylic reactant may be facilitated by the use of a higher concentration of catalyst composition.
Analogously, the size and position of the R4 and R5 substituents in intermediate (IIIb) and the size and position of the R6 and R7 substituents in intermediate (IVb) determine the relative position of R4 and R5, or R6 and R7, in the final product. A sterically bulky R4 or R5, or R6 or R7, substituent will result in the positioning of that substituent in a syn configuration in relation to R8 in the final product.
For example, assuming R4 is a sterically bulkier substituent than R5, intermediate (IIIb) 
will give rise to the products (Va) and (Vb) 
Similarly, assuming R6 is bulkier than R7, intermediate (IVb) will result in products (VIa) and (VIb) 
Looking at the four possible products above, it will be noted that in products (Va) and (VIa), the substituents R1 and R8 are in an anti configuration, while in products (Vb) and (VIb) they are in syn configuration. Steric interference prohibits the syn configuration from forming during the second Claisen rearrangement and, consequently, the anti configuration is highly preferred in the second reaction and the final product is a syn-anti configuration (e.g., syn between the bulkier substituent of the of the first rearrangement and the R1 group of the acid chloride (IIa) and anti between the R1 group of the acid chloride (IIa) and the R8 group of the acid chloride (IIb)).
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
All patents, patent applications, journal articles and other references cited herein are incorporated by reference in their entireties.
In the following example, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless indicated otherwise, temperature is in degrees C and pressure is at or near atmospheric.
General Information:
All non-aqueous reactions were performed using flame- or oven-dried glassware under an atmosphere of dry nitrogen. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego, Purification of laboratory Chemicals, Fourth Edition (Oxford, Butterworth-Heinemann, 1996). Non-aqueous reagents were transferred under nitrogen via syringe or cannula. Organic solutions were concentrated under reduced pressure on a Bxc3xcichi rotary evaporator. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl prior to use. N,N-diisopropylethylamine and dichloromethane were distilled from calcium hydride prior to use. Air sensitive solids were dispensed in an inert atmosphere glovebox. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still et al. (1978) J. Org. Chem. 43:2923. Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by fluorescence quenching or KMnO4 stain.
1H and 13C NMR spectra were recorded on Bruker DRX-500 (500 MHZ and 125 MHZ, respectively), AMX-400 (400 MHZ and 100 MHZ), or AMX-300 (300 MHZ and 75 MHZ) instruments, as noted, and are internally referenced to residual protio solvent signals. Data for 1H are reported as follows: chemical shift (xcex4 ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), integration, coupling constant (Hz) and assignment. Data for 13C are reported in terms of chemical shift. IR spectra were recorded on an ASI React-IR 1000 spectrometer and are reported in terms of frequency of absorption (cm1xe2x88x92). Mass spectra were obtained from the UC Berkeley Mass Spectral facility. Gas chromatography was performed on
Hewlett-Packard 5890A and 6890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using the following columns: Bodman Chiraldex xcex3-TA (30 mxc3x970.25 mm) and CandC Column Technologies CC-1701 (30 mxc3x970.25 mm).
General Procedure A:
A round-bottomed flask containing TiCl4.(THF)2 was charged with a solution of the with the allyl morpholine in CH2Cl2, followed by i-Pr2NEt. The reaction mixture was cooled to xe2x88x9220xc2x0 C. for 5 min or unless otherwise noted maintained at room temperature before a solution of the acid chloride in CH2Cl2 was added dropwise over 1 min. The resulting dark red solution was stirred until the allyl morpholine was completely consumed (4-6 h) as determined by TLC (EtOAc). The reaction mixture was then diluted with EtOAc (20 mL) and washed with aqueous IN NaOH (20 mL). The aqueous layer was then extracted with ethyl acetate (3xc3x9720 mL), and the combined organic layers washed with brine, dried (Na2SO4), and concentrated. The resulting residue was purified by silica gel chromatography (EtOAc) to afford the title compounds.